The focus of the proposed study will be to identify genetic variants in microRNAs which are significantly associated with risk of Non-Hodgkin's lymphoma (NHL). Our long-term goal is to identify a panel of miRNA SNPs that may serve as novel risk biomarkers in lymphomagenesis. Archived DNA samples from our previous population-based studies of NHL will be used for the pooled genetic analysis, which allows for a large sample size and sufficient power to detect genuine associations. miRNA cloning and a vector-based delivery system will also be employed to determine the impact of all identified variants on miRNA processing and downstream regulatory capacity. Each lymphoma-associated miRNA will be interrogated using whole-genome expression microarrays and genetic networking analyses, in order to determine which biological pathways are affected by miRNA gain-of-function, and to determine the impact of each variant, particularly within the context of lymphoma-relevant pathways. In addition, the pathways regulated by each lymphoma-associated miRNA will be used to identify novel biological mechanisms involved in the etiology of lymphoma, providing new areas of future research in chemoprevention and targeted therapies. To date, very few published molecular epidemiological studies have been performed to determine whether variants in miRNAs may be associated with human cancer risk at the population level. The proposed multidisciplinary project will investigate miRNAs from a molecular epidemiological and functional genetic perspective, and the information gleaned from these studies will provide population-based evidence for the miRNA-cancer connection, and will contribute significantly to furthering our understanding of the role of miRNAs in tumorigenesis. Since DNA samples are already available for this project, the proposed study can be conducted within a relatively short time period, and will represent an extremely efficient use of time and resources. The knowledge obtained from this study has the potential to: 1) identify novel biomarkers associated with NHL risk;2) advance our understanding of the biological mechanism involved in lymphomagenesis;and 3) provide new avenues of research which can be exploited to facilitate the development of novel chemopreventive and therapeutic strategies. PUBLIC HEALTH RELEVANCE: This work will be the first molecular epidemiologic study investigating miRNAs in non-Hodgkin's lymphoma (NHL) and will contribute significantly to advancing our understanding of the role of miRNAs in lymphomagenesis. Because of the availability of DNA samples from 2 population-based NHL case-control studies, this study is both time- and cost-effective. Both genetic association and functional analyses will be performed and the knowledge gained from this study will help us to identify new cancer biomarkers and facilitate the development of novel diagnostic and therapeutic strategies.